Bcl-2 family inhibitors sensitize human cancer models to therapy.

Publication date: Jul 17, 2023

BH3 mimetics, targeting the Bcl-2 family anti-apoptotic proteins, represent a promising therapeutic opportunity in cancers. ABT-199, the first specific Bcl-2 inhibitor, was approved by FDA for the treatment of several hematological malignancies. We have recently discovered IS21, a novel pan BH3 mimetic with preclinical antitumor activity in several tumor types. Here, we evaluated the efficacy of IS21 and other BH3 mimetics, both as single agents and combined with the currently used antineoplastic agents in T-cell acute lymphoblastic leukemia, ovarian cancer, and melanoma. IS21 was found to be active in T-cell acute lymphoblastic leukemia, melanoma, lung, pancreatic, and ovarian cancer cell lines. Bcl-xL and Mcl-1 protein levels predicted IS21 sensitivity in melanoma and ovarian cancer, respectively. Exploring IS21 mechanism of action, we found that IS21 activity depends on the presence of BAX and BAK proteins: complexes between Bcl-2 and Bcl-xL proteins and their main binding partners were reduced after IS21 treatment. In combination experiments, BH3 mimetics sensitized leukemia cells to chemotherapy, ovarian cancer cells and melanoma models to PARP and MAPK inhibitors, respectively. We showed that this enhancing effect was related to the potentiation of the apoptotic pathway, both in hematologic and solid tumors. In conclusion, our data suggest the use of inhibitors of anti-apoptotic proteins as a therapeutic strategy to enhance the efficacy of anticancer treatment.

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Concepts Keywords
Cancer Activity
Fda Anti
Is21 Apoptotic
Ovarian Bcl
Therapy Bh3


Type Source Name
disease MESH cancer
disease MESH hematological malignancies
disease MESH ovarian cancer
disease MESH melanoma
pathway KEGG Melanoma
disease MESH leukemia
drug DRUGBANK D-Alanine
disease MESH acute lymphoblastic leukemia
disease MESH Death
pathway KEGG Apoptosis
drug DRUGBANK Venetoclax
disease MESH lymphoma
drug DRUGBANK Coenzyme M
drug DRUGBANK Navitoclax
drug DRUGBANK Platinum
drug DRUGBANK Paclitaxel
drug DRUGBANK L-Glutamine
drug DRUGBANK Streptomycin
drug DRUGBANK Dabrafenib
drug DRUGBANK Trametinib
drug DRUGBANK Olaparib
drug DRUGBANK Dimethyl sulfoxide
drug DRUGBANK Doxorubicin
drug DRUGBANK Vincristine
drug DRUGBANK Methylene blue
drug DRUGBANK Ethanol
drug DRUGBANK Aspartame
drug DRUGBANK Gentian violet cation
drug DRUGBANK Water
drug DRUGBANK Sodium lauryl sulfate
drug DRUGBANK MK-212
disease MESH pancreatic carcinoma
drug DRUGBANK Proline

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